Ophthalmic Emulsions Containing Prostaglandins

ABSTRACT

Cationic ophthalmic oil-in-water type emulsions, include colloid particles having an oily core surrounded by an interfacial film. The emulsion includes at least one cationic agent and at least one non ionic surfactant, the oily core including a prostaglandin selected from the group consisting essentially of latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandinE 2 , or a mixture thereof, for treating ocular hypertension and/or glaucoma. These emulsions have the property to increase the chemical stability of prostaglandins.

The present invention concerns ophthalmic cationic oil-in-water typeemulsions containing prostaglandins.

In the present invention, the term <<prostaglandin>> is indifferentlyused for prostaglandin, its precursors or analogs.

The present invention is of particular interest for prostaglandin F_(2α)analogs such as in particular latanoprost, unoprostone isopropyl,travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E₂ or a mixtureof two or more thereof.

By <<ophthalmic>> it is meant an emulsion intended to be administered tothe eye and which presents a pharmaceutical effect; preferably, it istopically applied.

It is known to use prostaglandins in ophthalmic preparations in order totreat glaucoma. The problem encountered with prostaglandins, inparticular with latanoprost, is that their concentration lowers in theformulation overtime.

U.S. Pat. No. 6,011,062, U.S. Pat. No. 5,688,819, U.S. Pat. No.5,849,792, U.S. Pat. No. 4,599,353 describe the use of severalprostaglandin analogs for treating glaucoma and ocular hypertension.U.S. Pat. No. 5,849,792 discloses the use of a non ionic surfactant(polyethoxylated castor oil) to enhance the prostaglandin's chemicalstability.

However, the proposed solutions to enhance the stability ofprostaglandins are not completely satisfactory. Furthermore, use of BAKor other quaternary ammonium as preservative agent for prostaglandins inophthalmic preparations has been challenged, since C. Debbasch et al. inInvestigative Ophthalmology & Visual Science, March 2001, Vol 42 n°3,demonstrated important toxicity of long term use of BAK and/or otherquaternary ammoniums.

Latanoprost, Travoprost, Bimatoprost, unoprostone isopropyl, tafluprost,8-isoprostaglandinE2, like most of the prostaglandin analogs, are almostinsoluble in water. So, it is interesting to provide ophthalmic vehiclessuitable for delivering hydrophobic drugs. In recent years, oil-in-watertype emulsions, in particular emulsions having droplets of a submicronsize (hereinafter “submicron emulsions”) gained increasing importance.These emulsions are in general anionic emulsions. The major hurdle indeveloping topically applied ophthalmic drug delivery systems such asemulsions is the relatively low bioavailability of the drugs. To addressthis issue, cationic emulsions have been developed as topical ophthalmicvehicles; they have the advantage of increasing the bioavailability ofthe drugs by electrostatic attraction between the emulsions's positivecharge and the negatives charges carried at the eye surface. However,stabilizing emulsions, including submicron emulsions, may be a concernfor one skilled in the art. One known approach to stabilize an emulsionis to confer an electrostatic charge to the droplets surface which willresult in droplet repulsion and less droplet coalescence. Colloidalparticles dispersed in a solution are electrically charged due to theirionic characteristics and dipole attributes. This charge, which can benegative resulting in anionic emulsions or positive producing cationicemulsions (Klang et al., Pharm. Dev. Technology 2000, 5, 521-532) isknown in the art as the “zeta potential”. The zeta potential is ameasure of the magnitude of the repulsion or attraction betweenparticles (Washington, Adv. Drug Deliv. Reviews 1996, 20:131-145).

Of particular interest are the following patents dealing with cationicemulsions for topical ocular administration:

U.S. Pat. No. 6,007,826 discloses a cationic oil-in-water emulsion whichcomprises colloid particles with a positively charged interfacial film.The interfacial film is formed by cationic lipids (0.05-3% by weight)such as C₁₀-C₁₄ primary alkylamines (disclosed are stearylamine oroleylamine), C₁₀-C₂₄ primary alkanolamine or a cholesterol betainate;phospholipids (0.5-3%) and non-ionic surfactants from the groupconsisting of poloxamers, tyloxapol, polysorbate, and polyoxyethylenefatty acid esters (0.05-3%). The concentration of the oily core ismaintained within the 3-20% range.

U.S. Pat. No. 6,007,826 emulsions zeta potential are not stable tothermal stress (see Tamilvanan et al., STP Pharma Sciences 2001,11:421-426 and Example 12).

Thus, there is still a need in ophthalmic prostaglandin products whichare at least as efficient as the commercial products, which present anenhanced chemical stability of the prostaglandin, which are less toxic,which are more physically and chemically stable than conventionalproducts, i.e. which are stable overtime and which present a goodtolerability for the patient.

By overtime in the meaning of this invention, it is meant a durationexceeding 1 year, preferably exceeding 2 years, more preferablyexceeding 3 years.

By “good tolerability” in the present the invention, it is understoodthat the ratio therapeutic benefit to ocular discomfort is acceptable bythe patient, and preferably similar to a placebo or NaCl 0.9% solution.It is generally accepted that in order to show good ocular tolerabilitythe cation content within the formulation should not exceed 0.1%,preferably not exceed 0.05% and even more preferably should not exceed0.03%. Quaternary amines such as benzalkonium chloride, benzododeciniumbromide and benzethonium chloride are allowed by health authorities forophthalmic administration up to concentration of approximately 0.03%(Furrer et al., Eur. J. Pharm. Biopharm. 2002, 53:263-280).

This invention thus relates to a cationic ophthalmic oil-in-water typeemulsion, which comprises colloid particles having an oily coresurrounded by an interfacial film,

said emulsion comprising at least one cationic agent and at least onenon ionic surfactant selected from selected from the group consisting ofpoloxamers, tyloxapol, polysorbates, polyoxyethylene castor oilderivatives, sorbitan esters, polyoxyl stearates and a mixture of two ormore thereof, said oily core comprising a drug selected from the groupconsisting of latanoprost, unoprostone isopropyl, travoprost,bimatoprost, tafluprost, 8-isoprostaglandin E₂ or a mixture of two ormore thereof, and said emulsion being free of water-soluble polymerselected from a polyvinyl compound, a water-soluble cellulose compoundand a polysaccharide.

In a prefered embodiment the emulsions of the invention includeslatanoprost, as only drug or in combination with one or moreprostaglandin selected from the group consisting of unoprostoneisopropyl, travoprost, bimatoprost, tafluprost and 8-isoprostaglandinE₂.

According to a preferred embodiment, the emulsion of the invention isfree of water-soluble polymer selected from (1) a polyvinyl compoundsuch as polyvinylalcohol and polyvinylpyrrrolidone, (2) a water-solublecellulose compound such as methylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, and/or sodium cellulose and (3) apolysaccharide selected from alginic acid, xanthan gum, carrageenan, andchitosan.

According to an embodiment, the emulsion includes polyoxyethylene castoroil derivatives, especially polyethoxylated castor oil such as forexample PEG PEG-30 PEG-35 PEG-50 castor oils.

According to another embodiment, the emulsion is free of anypolyoxyethylene castor oil derivatives.

The term “free of” in combination with a compound or a list of compound,means that the emulsion does not contain any compound of that kind.

According to a specific embodiment of the invention, the emulsion mayfurther comprise an anti-inflammatory compound, preferably a nonsteroidal anti-inflammatory compound or a omega-3 fatty acid.Anti-inflammatory agents may be chosen in the group comprising COX-2inhibitors, salicylates, 2-arylpropionic acids, N-arylanthranilic acids,oxicams, sulphonanilides, pyrazolidines derivatives, arylalkanoic acids,3-benzolphenylacetic acids and derivatives; steroids such as cortisone,hydrocortisone, prednisone, prednisolone, methylprednisone,fluoromethalone, medrysone, betamethasone, loteprednol, flumethasone,mometasone, testosterone, methyltestosterone, danazol, beclomethasone,dexamethasone, dexamethasone palmitate, tramcinolone, triamcinoloneacetonide, fluocinolone, fluocinolone acetonide, difluprednate,rimexolone.

In the emulsions of this invention, the chemical stability ofprostaglandins is enhanced. Without being linked by any theory, it isbelieved that since the prostaglandin is solubilized in the oily core ofthe emulsion, it is less available to contact with agents enhancing itsdegradation. Said stability is defined as the extent to which a productretains, within specified limits and throughout its period of storageand use (i.e., its shelf life), the same properties and characteristicsthat it possessed at the time of manufacture. The purpose of stabilitytesting is to provide evidence on how the quality of a drug substance ordrug product varies overtime under the influence of a variety ofenvironmental factors such as temperature, humidity and light, andenables recommended storage conditions, re-test periods and shelf livesto be established.

Although real-time stability studies include an evaluation of thosefactors that ultimately affect the expiration date of the drugs, theyare time and cost-consuming. Conventionally, accelerated stabilitystudies are used for predicting the shelf life of pharmaceuticalproducts. Such accelerated studies subject the systems to a temperatureof 40° C. during 6 months.

In order to understand the intrinsic stability mechanism of the moleculeby establishing degradation pathways and identifying the likelydegradation products, and thus to adjust the analytical procedures to beused, the Applicant has developed stress stability testing during whichthe emulsions are subjected to extreme conditions that is a temperatureof 80° C. during specified period of time.

The amount of prostaglandins present in the oily core of the emulsionaccording to the invention depends on the nature of the prostaglandinsand to the intended use. According to an embodiment, the amount of thedrug(s) selected from the group comprising or consisting of latanoprost,unoprostone isopropyl, travoprost, bimatoprost, tafluprost,8-isoprostaglandin E₂ or a mixture of two or more thereof is of 0.001%to 1% w/w, preferably of 0.002% to 0.3% w/w and even more preferably of0.004% to 0.15% w/w.

In the present application, percentages are expressed in weight relativeto the total weight of the emulsion (% w/w).

The concentration of the cationic agent is comprised between 0.001 to0.1% w/w, preferably between 0.002 to 0.05% w/w and even more preferablybetween 0.003 to 0.03% w/w.

The concentration of the oily core is not higher than 7% w/w, preferablybetween 0.5 to 5% w/w and even more preferably between 1 to 3% w/w.

The concentration of the non-ionic agent is less than 1% w/w, comprisedpreferably between 0.01 to 0.6% w/w. The cationic agent is selected inthe group comprising or consisting of C10-C24 primary alkylamines,tertiary aliphatic amines, quaternary ammonium compounds selected fromthe group comprising benzalkonium halide, lauralkonium halide,cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, myristalkoniumhalide, stearalkonium halide or a mixture of two or more thereof, halidebeing preferably chloride or bromide, cationic lipids, amino alcohols,biguanide salts selected from the group comprising or consisting ofchlorhexidine and salts thereof, polyaminopropyl biguanide, phenformin,alkylbiguanide or a mixture of two or more thereof, cationic compoundsselected from 1,2-dioleyl-3-trimethylammcnium-propane,1,2-dioleoyl-sn-glycero-phosphatidylethanolamine, cationic glycosphingo-lipids or cationic cholesterol derivatives, or mixtures of two or morethereof.

According to a specific embodiment of the invention, the emulsion doesnot contain chlorhexidine and salts thereof.According to a preferred embodiment, the cationic agent is selected fromthe group comprising benzalkonium chloride, lauralkonium chloride,benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof.According to a most preferred embodiment, the cationic agent included inthe emulsion of the inventionis selected from at least one quaternaryammonium halide in which the nitrogen atom is substituted by at leastone alkyl group having at least 14 carbon atoms. According to a specificembodiment of the invention, the emulsion contains benzalkonium halideas only cationic agent.

The oily phase of the emulsion may comprise one or more componentsselected from the group comprising or consisting of vegetable oils (i.e.soybean oil, olive oil, sesame oil, cotton seed oil, castor oil, sweetalmond oil), mineral oil (i.e. petrolatum and liquid paraffin), mediumchain triglycerides (MCT) (i.e. a triglyceride oil in which thecarbohydrate chain has about 8-12 carbon atoms), oily fatty acid,isopropyl myristate, oily fatty alcohols, esters of sorbitol and fattyacids, oily sucrose esters, and in general any oily substance which isphysiologically tolerated.

According to an embodiment of the invention, the oil phase has a iodinevalue of less than 50, preferably equal or less than 15, more preferablyequal or less than 5 and even more preferably equal or less than 1. Inthis embodiment, the oil phase comprises one or more components selectedfrom the group comprising or consisting of mineral oil such as forexample petrolatum and liquid paraffin, and light mineral oil, mediumchain triglycerides (MCT) which is generally defined as a triglycerideoil in which the carbohydrate chain has about 8-12 carbon atoms, coconutoil; hydrogenated oils comprising hydrogenated cottonseed oil,hydrogenated palm oil, hydrogenate castor oil or hydrogenated soybeanoil; polyoxyethylene hydrogenated castor oil derivatives comprisingpoluoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oilor polyoxyl-100 hydrogenated castor oil.

According to a preferred embodiment of the invention, the majorcomponent of the oily phase will be either vegetable oil, preferablywith a iodine value of less than 50, and/or MCT. Fatty acids or fattyalcohols may be included in cases where the hydrophobic substance to becarried by the emulsion is not sufficiently soluble in the oily phase.

Examples of MCT oil which may be used in emulsions of the presentinvention are TCM™ (Société des Oléagineux, France), Miglyol 812™(Dynamit Novel, Sweden).

The non-ionic surfactant is selected from the group comprising orconsisting of poloxamers, tyloxapol, polysorbates, polyoxyethylenecastor oil derivatives, sorbitan esters, polyoxyl stearates and amixture of two or more thereof.

According to another preferred embodiment of the invention, the cationicophthalmic emulsion comprises benzalkonium chloride as cationic agentand tyloxapol as non-ionic surfactant.

According to still another preferred embodiment, the emulsion containsbenzalkonium chloride as cationic agent and a combination of tyloxapoland poloxamer as non-ionic surfactants.

The emulsion may also contain antioxidant such as Vitamin E, isotonicagent, buffering agent, preservative, etc.

According to an embodiment of the invention, the emulsion includes atleast one preservative.According to another embodiment of the invention, the emulsion does notcontain any preservative.The colloidal particles of the emulsions according to the invention havean average particle size of equal or less than 1 μm, advantageouslyequal or less than 300 nm, more advantageously in the range of 100 to250 nm.The emulsion of the invention may be conditioned in monodosis containersor in multidosis containers.According to an embodiment, the containers for carrying the emulsion ofthe invention are made of glass, plastic materials, resins or the like.

According to another embodiment of the invention, the cationicophthalmic emulsion may comprise a further pharmaceutically activesubstance, either in the oily core or in the aqueous part of theemulsion. This pharmaceutically active substance may be anantiglaucomateous active substance, which may be selected from the groupcomprising beta-blockers such as levobunolol, befundol, metipranolol,forskolin, cartrolol, timolol; inhibitors of carbonic anhydrase such asbrinzolamide, dorzolamide, acetazolamide, methazolamide,dichlorophenamide; sympathomimetics such as brimonidine, apraclonidine,dipivefrine, epinephrine; parasympathomimetics such as pilocarpine;cholinesterase inhibitors such as physostigmine, echothiophate and/ortheir derivatives; and/or optically acceptable salts thereof.

The emulsions according to the invention are physically stable overtimeas defined hereabove and keep a positive zeta potential in the specificmeasurement conditions as described in Tests A, B, C and/or D.

According to the invention, the emulsions do not contain a sufficientamount of any substances susceptible of affecting the zeta potentialovertime. Advantageously, the emulsions of the invention do not containphospholipids.

Substances susceptible of affecting the zeta potential may bephospholipids, and any substances which become negatively charged uponstorage.

The amount of substances affecting the zeta potential overtime must besuch that at any time, the amount of positive charge is above the amountof negative charges.

Zeta Potential

Zeta potential measures a physical property which is exhibited by anyparticle in suspension. Zeta potential can be used to predict behaviourof the suspension in different environments, to optimize theformulations of suspensions and emulsions as well as to predict overtimestability.

In order to avoid the emulsion droplets to adhere to one another andform aggregates of successively increasing size, it is necessary toconfer repulsive forces to the particles. One of the means to conferrepulsive forces to a colloidal system is by electrostatic or chargestabilization. Electrostatic or charge stabilization has the benefits ofstabilizing a system by simply altering the concentration of ions in thesystem. This is a reversible and inexpensive process.

There might by many origins of this surface charge depending upon thenature of the particle and its surrounding medium but the most importantmechanisms are the ionisation of surface groups or the adsorption ofcharged ions.

The interaction of particles in polar liquids is not governed by theelectrical potential at the surface of the particle, but by theeffective potential of the particle and its associated ions. To utilizeelectrostatic control of dispersions, it is the zeta potential of theparticle that must be measured rather than its surface charge. Chargedparticles will attract ions of opposite charge in the dispersant. Ionsclose to the surface are strongly bound; those further away form a morediffuse region. Within this region is a notional boundary, known as theslipping plane, within which the particle and ions act as a singleentity. The potential at the slipping plane is known as the zetapotential. It has long been recognised that the zeta potential is a verygood index of the magnitude of the interaction between colloidalparticles and measurements of zeta potential are commonly used to assessthe stability of colloidal systems. The zeta potential measured in aparticular system is dependent on the chemistry of the surface, and alsoof the way it interacts with its surrounding environment. Therefore zetapotential must always be studied in a well defined environment(specifically pH and ionic strength).

Electrophoretic Mobility

An important consequence of the existence of electrical charges on thesurface of particles is that they interact with an applied electricfield. These effects are collectively defined as electrokinetic effects.If the motion is induced in a particle suspended in a liquid under theinfluence of an applied electric field, it is more specifically namedelectrophoresis. When an electric field is applied across anelectrolyte, charged particles suspended in the electrolyte areattracted towards the electrode of opposite charge. Viscous forcesacting on the particles tend to oppose this movement. When equilibriumis reached between these two opposing forces, the particles move withconstant velocity. The velocity is dependent on the strength of electricfield or voltage gradient, the dielectric constant of the medium, theviscosity of the medium and the zeta potential. The velocity of aparticle in a unit electric field is referred to as its electrophoreticmobility. Zeta potential is related to the electrophoretic mobility bythe Henry equation:

$U_{E} = \frac{2\; ɛ\; {{zf}\left( {\kappa \; a} \right)}}{3\; \eta}$

where U_(E)=electrophoretic mobility, z=zeta potential, ε=dielectricconstant, η=viscosity and f(κa)=Henry's function.

Electrophoretic determinations of zeta potential are most commonly madein aqueous media and moderate electrolyte concentration. f(κa) in thiscase is 1.5, and this is referred to as the Smoluchowski approximation.Therefore calculation of zeta potential from the mobility isstraightforward for systems that fit the Smoluchowski model, i.e.particles larger than about 0.2 microns dispersed in electrolytescontaining more that 10−3 molar salt. For small particles in lowdielectric constant media (eg non-aqueous media), f(κa) becomes 1.0 andallows an equally simple calculation. This is referred lo as the Huckelapproximation.

Tests A, B, C and D

Test A consists in measuring the stability of the emulsion zetapotential under thermal stress conditions.

Zeta potential of the emulsion is measured at T=0, i.e. as soon as theemulsion has been prepared, the obtained value being named Z. Glassvials (Type I) of 10 ml effective capacity containing between 5-10 ml ofemulsion and sealed under nitrogen atmosphere (without bubbling) arestored at 80° C.

Then at T=15 hours the zeta potential Z_(15h) is measured.

The value δA=Z_(15h)-Z₀ is then calculated.

For each measurement of the zeta potential, it is operated as follows:

The zeta potential of the emulsion droplet surface is determined byelectrophoretic mobility in an apparatus such as a Malvern Zetasizer2000 (Malvern Instruments, UK) equipped with suitable software andcalibrated with the supplied standard.

The emulsion is diluted in double distilled water if needed in order toobtain the scattering intensity allowing optimal particle detection. Thesample count rate should be between 100 to 1000 KCps, in homodynedetection (if heterodyne detection is used, the contribution of thereference beam should be deduced). Three consecutive measurements areperformed at 25° C. using a constant cell drive of 150 mV. Theelectrophoretic mobility is converted into zeta potential values throughthe Smoluchowsky equation, using the dielectric constants and viscosityof water. The measured value corresponds to the average of the 3obtained values.

It is considered that the emulsion meets zeta potential stability Test Aif δA is less than the standard error of measurements, preferably lessthan 10 mV, and even more preferably less than 5 mV.

According to an advantageous embodiment, the ophthalmic emulsionaccording to the invention meets zeta potential stability Test B.

Test B is similar to Test A except that the emulsion is stored during 48hours at 80° C., the zeta potential Z₂ is measured on day 2 and δB=Z₂-Z₀is calculated. The emulsion is considered as meeting the requirements ofzeta potential stability test B if δB is less than the standard error ofmeasurements, preferably less than 10 mV, and even more preferably lessthan 5 mV.

According to a more advantageous embodiment of the invention, theophthalmic emulsion according to the invention meets zeta potentialstability Test C.

Test C is similar to Test A except that the emulsion is stored during 7days at 80° C., the zeta potential Z₇ is measured on day 7 and δC=Z₇-Z₀is calculated. The emulsion is considered as meeting the requirements ofzeta potential stability test C if δC is less than the standard error ofmeasurements, preferably less than 10 mV, and even more preferably lessthan 5 mV.

According to a still more advantageous embodiment of the invention, theophthalmic emulsion according to the invention meets zeta potentialstability Test D.

Test D is similar to Test A except that the emulsion is stored during 14days at 80° C., the zeta potential Z₁₄ is measured on day 14 andδD=Z₁₄-Z₀ is calculated. The emulsion is considered as meeting therequirements of zeta potential stability test D if δD is less than thestandard error of measurements, preferably less than 10 mV, and evenmore preferably less than 5 mV.

According to another aspect, the invention relates to a process formanufacturing the emulsions here-above described.

The emulsions are prepared as follows:

-   -   the prostaglandin is dissolved into the oily phase, which is        optionally added with another hydrophobic ophthalmologically        active ingredient,    -   the aqueous phase, optionally added with another hydrophilic        ophthalmologically active ingredient, is rapidly added to the        oily phase,    -   the coarse emulsion obtained is rapidly heated, preferably at        75° C.,    -   the emulsion droplet size is then decreased by any suitable        means known by one skilled in the art, for example by shear        mixing,    -   the emulsion temperature is cooled down to 20° C. using an ice        bath and then homogenized    -   pH is adjusted to 7-8,    -   the emulsion is sterilized.

The inventions also relates to the use of a cationic ophthalmicoil-in-water emulsion as hereabove described for the preparation of anophthalmic composition for treating ocular hypertension and/or fortreating glaucoma.

According to another aspect, the invention relates to ophthalmicformulation comprising an emulsion as previously described, optionallyin combination with an ophthalmologically acceptable carrier, in theform of eye drops, eye ointment, ophthalmic gel. In said ophthalmicformulation there may be a pharmaceutically effective amount of anactive ingredient in or within the ophthalmologically acceptablecarrier.

The invention is also directed to a delivery device selected from thegroup comprising lenses, ocular patch, implant, insert, said devicecontaining an emulsion as previously described.

The invention is further illustrated by the examples below.

EXAMPLES

In the following examples, the following abbreviations are used:Medium Chain Triglycerides MCT: TCM™ (Société des Oléagineux)BAK: benzalkonium chloride (FeF Chemicals, Denmark)

Lutrol: Lutrol F68™ (BASF) Tyloxapol : Triton WR1339 (Ruger Chemicals,USA)

Z29 : latanoprost

Example 1

Emulsion Z29EM002 Z29EM003 Z29EM005 Z29EM007 Composition 1% MCT 1% MCT0.02% BAK 0.02% BAK 0.1% Lipoid 0.1% Tyloxapol 1% MCT 1% MCT 0.05% OA0.05% OA 0.16% Tyloxapol 0.3% Tyloxapol 0.005% vit E 0.005% vit E 0.01%vit E 0.01% vit E 0.25% Lutrol 0.25% Lutrol 0.25% Lutrol 0.1% Lutrol2.25% Glycerin 2.25% Glycerin 2.25% Glycerin 2.25% Glycerin Water to100% Water to 100% Water to 100% Water to 100% Z29 0.005% Z29 0.005% Z290.005% Z29 0.005% Zeta potential T0: 22.4 T0: 21.8 stress test T7: 24.1T7: 18.8 T15: 19.8 T15: 18.9 Droplet size T0: 160 T0: 212 (nm) T7: 173T7: 225 stress test T15: 185 T15: 236 Emulsion Z29EM008 Z29EM011Composition 0.02% BAK 0.01% BAK 1% MCT 1% MCT 0.3% Tyloxapol 0.3%Tyloxapol 0.1% Lutrol 0.1% Lutrol 2.25% Glycerin 2.25% Glycerin Water to100% Water to 100% Z29 0.005% Z29 0.005% Zeta T0: 20.6 potential T7:18.5 stress test T15: 16.2 Droplet size T0: 201 stress test T7: 212 T15:216The oily phase components including 0.005% latanoprost (named Z29 in theTables) were successively weighed in the same beaker and thenmagnetically stirred under a slight heating (40° C.) until a slightlyviscous phase is obtained. Aqueous phase components were successivelyweighed in the same beaker and then magnetically stirred under a slightheating (40° C.) until a transparent, limpid and fluid phase isobtained. Both phases were heated to 65° C. The coarse emulsion wasformed by rapid addition of the aqueous phase in the oily phase and wasthen rapidly heated to 75° C. The aqueous phase and coarse emulsionbeakers were protected by a film to avoid any water evaporation. Theemulsion was white and slightly transparent. The emulsion droplet sizewas then decreased by a 5 minutes high shear mixing with a POLYTRON PT6100. The emulsion became milky. The emulsion temperature was cooleddown to 20° C. using an ice bath.The final emulsion was obtained by homogenization in a microfluidizer(C5, Avestin) using continuous cycles for 5 min at a pressure of 10,000psi. The emulsion was milky, very fluid and did not adhere on the glass.The emulsion temperature was decreased to 25° C. Its pH was measured andthen adjusted to 7.0 using a 0.1 M HCl or 0.1 M NaOH solution. Emulsionwas conditioned in glass vials with nitrogen bubbling and thensterilized in an autoclave 20 minutes at 121° C.The mean particle size of the emulsions droplets was determined byquasi-elastic light scattering after dilution in water using a HighPerformance Particle Sizer (Malvern Instruments, UK).The electrophoretic mobility was measured at 25° C. in a MalvernZetasizer 2000 (Malvern Instruments, UK) following a 1:200 dilution indouble distilled water as detailed above and converted into zetapotential through the Smoluchowski equation.

Example 2

Latanoprost stability improvement in emulsion compared to commercialproduct (Xalatan®)The chemical stability of latanoprost within the emulsion was comparedto the commercial product Xalatan® at 80° C. for 14 days (FIG. 1).Prostaglandin contents were analysed by an HPLC-UV method.In emulsions according to the invention, latanoprost is chemicallystabilized.

Example 3

In vivo studies demonstrating that latanoprost emulsion is as efficientas the commercial product (Xalatan®) in reducing IOP (intraocularpressure)

Methods: Eight adult female cynomolgus monkeys, each weighing 3-6 kg, inwhich glaucoma had been induced by diode laser photocoagulation of themid-trabecular meshwork, were used in this study. Intraocular pressure(IOP) was measured at 0 hr (before drug administration) and then hourlyuntil 6 hrs after drug administration for one baseline day, onevehicle-treated day, and treatment days 1, 3, and 5 with 30 μl ofZ29EM007 (similar to the emulsion described in Example 1) or 0.005%Latanoprost (Xalatan; Pharmarcia & Upjohn, Kalamazoo, Mich.).The products were topically applied to the glaucomatous eye once dailyfor 5 consecutive days in a crossover design with a washout period atleast 2 weeks between the two drugs.Results: Once daily administration of both Z29EM007 and Xalatan for 5days significantly (p<0.005) reduced IOP from 1 hr to 5 hrs after thefirst dose compared to the vehicle treatment day (FIG. 2).The ocular hypotensive effect was enhanced by repeated dosing for bothZ29EM007 and Xalatan. No statistical difference of IOP reduction(p>0.80) was observed during the 5 days treatment when comparingZ29EM007 and Xalatan. IOP on the baseline day and vehicle-treated daywas not statistically different between the two drugs (p>0.90).Latanoprost in the emulsions according to the invention is as efficientas commercially available Xalatan™.

1. A cationic ophthalmic oil-in-water type emulsion, which comprisescolloid particles having an oily core surrounded by an interfacial film,said emulsion comprising at least one cationic agent and at least onenon ionic surfactant selected from the group consisting of poloxamers,tyloxapol, polysorbates, polyoxyethylene castor oil derivatives,sorbitan esters, polyoxyl stearates and a mixture of two or morethereof, said oily core comprising a drug selected from the groupconsisting of latanoprost, unoprostone isopropyl, travoprost,bimatoprost, tafluprost, 8-isoprostaglandm E₂ or a mixture of two ormore thereof said emulsion being free of water-soluble polymer selectedfrom a polyvinyl compound, a water-soluble cellulose compound and apolysaccharide.
 2. A cationic ophthalmic oil-in-water type emulsionaccording to claim 1, wherein the drug is latanoprost.
 3. A cationicophthalmic oil-in-water type emulsion according to claim 1, saidemulsion being free of water-soluble polymer selected from (1) apolyvinyl compound such as polyvinylalcohol and polyvinylpyrrolidone,(2) a water-soluble cellulose compound such as methylcellulose,hydroxyethylcellulose, hydroxypropylmethylcellulose, and/or sodiumcellulose and (3) a polysaccharide selected from alginic acid, xanthangum, carrageenan, and chitosan.
 4. A cationic ophthalmic emulsionaccording to claim 1, comprising at least one further pharmaceuticallyactive substance, either in the oily core or in the aqueous part of theemulsion.
 5. A cationic ophthalmic oil-in-water type emulsion accordingto claim 1, further comprising an anti-inflammatory compound, preferablya non steroidal anti-inflammatory compound or a omega-3 fatty acid.
 6. Acationic ophthalmic oil-in-water type emulsion according to claim 1,wherein the emulsion further comprise at least one furtherantiglaucomateous pharmaceutically active substance selected from thegroup comprising beta-blockers such as levobunolol, befundol, forskolin,metipranolol, cartrolol, timolol; inhibitors of carbonic anhydrase suchas bnnzolamide, dorzolamide, acetazolamide, methazolamide,dichlorophenamide; sympathomimetics such as brimomdine, apraclomdine,dipivefrine, epinephrine; parasympathomimetics such as pilocarpine;cholinesterase inhibitors such as physostigmine, echothiophate and/ortheir derivatives; and/or optically acceptable salts thereof.
 7. Acationic ophthalmic oil-in-water type emulsion according to claim 1,wherein the amount of the drug selected from the group consisting oflatanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost,8-isoprostaglandm E₂ or a mixture of two or more thereof in the oilycore is 0.001 to 1% w/w, preferably 0.002 to 0.3% w/w and even morepreferably 0.004 to 0.15% w/w.
 8. A cationic ophthalmic oil-in-watertype emulsion according to claim 1, wherein the concentration of thecationic agent is comprised between 0.001 to 0.1% w/w, preferablybetween 0.002 to 0.05% w/w and even more preferably between 0.003 to0.03% w/w.
 9. A cationic ophthalmic oil-in-water type emulsion accordingto claim 1, wherein the concentration of the oily core is not higherthan 7% w/w, preferably between 0.5 to 5% w/w and even more preferablybetween 1 to 3% w/w.
 10. A cationic ophthalmic emulsion according toclaim 1, wherein the concentration of the non-ionic agent is less than1% w/w, comprised preferably from 0.01 to 0.6% w/w.
 11. A cationicophthalmic oil-in-water emulsion according claim 1, wherein the cationicagent is selected in the group consisting of C10-C24 primaryalkylamines, tertiary aliphatic amines, quaternary ammonium compounds,cationic lipids, amino alcohols, biguanide salts, cationic compounds anda mixture of two or more thereof.
 12. A cationic ophthalmic oil-in-wateremulsion according to claim 11, wherein the biguanide salt is selectedfrom the group comprising chlorhexidine and salts thereof,polyaminopropyl biguanide, phenformin, alkylbiguanide or a mixture oftwo or more thereof.
 13. A cationic ophthalmic oil-in-water emulsionaccording to claim 11, wherein the quaternary ammonium compound isselected from the group comprising benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, rnyristylalkoniumhalide, stearalkonium halide or a mixture of two or more thereof, halidebeing preferably chloride or bromide.
 14. A cationic ophthalmic emulsionaccording to claim 1, wherein said cationic agent is selected from thegroup comprising benzalkonium chloride, lauralkonium chloride,benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof.15. A cationic ophthalmic emulsion according to claim 1, wherein thecationic agent is selected from at least one quaternary ammonium halidein which the nitrogen atom is substituted by at least one alkyl grouphaving at least 14 carbon atoms.
 16. A cationic ophthalmic emulsionaccording to claim 1, wherein the oil phase has a iodine value of lessthan 50, preferably equal or less than 15, more preferably equal or lessthan 5 and even more preferably equal or less than
 1. 17. A cationicophthalmic emulsion according to claim 16, wherein the oil phasecomprises one or more components selected from the group consisting ofmineral oil and light mineral oil, medium chain triglycerides (MCT),coconut oil; hydrogenated oils comprising hydrogenated cottonseed oil,hydrogenated palm oil, hydrogenate castor oil or hydrogenated soybeanoil; polyoxyethylene hydrogenated castor oil derivatives comprisingpoluoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oilor polyoxyl-100 hydrogenated castor oil.
 18. A cationic ophthalmicemulsion according to claim 1, wherein the oil is MCT.
 19. A cationicophthalmic emulsion according to claim 1, comprising benzalkoniumchloride as cationic agent and tyloxapol as non-ionic surfactant.
 20. Acationic ophthalmic emulsion according to claim 1, wherein the emulsioncontains benzalkonium chloride as cationic agent and a combination oftyloxapol and poloxamer.
 21. A cationic ophthalmic emulsion according toclaim 1, wherein said colloidal particles have an average particle sizeof equal or less than 1 μm, advantageously equal or less than 300 nm,more advantageously in the range of 100 to 250 nm.
 22. A cationicophthalmic oil-in-water type emulsion according to claim 1, wherein theemulsion meets zeta potential stability Test A requirements.
 23. Anophthalmic emulsion according to claim 1, which meets zeta potentialstability Test B requirements.
 24. An ophthalmic emulsion according toclaim 1, which meets zeta potential stability Test C requirements. 25.An ophthalmic emulsion according to claim 1, which meets zeta potentialstability Test D requirements.
 26. (canceled)
 27. Ophthalmic formulationcomprising an emulsion according to claim 1, optionally in combinationwith an ophthalmologically acceptable carrier, said formulation being inthe form of eye drops, eye ointment, ophthalmic gel.
 28. Delivery deviceselected from the group comprising lenses, ocular patch, implant,insert, said device containing an emulsion according to claim
 1. 29.Method of treating ocular hypertension and/or glaucoma, which comprisesadministering an effective amount of a cationic ophthalmic oil-in-wateremulsion according to claim 1 to a subject in need thereof.